Neonatal jaundice is common and usually not concerning when it is secondary to unconjugated hyperbilirubinemia, below the neurotoxic level, and resolves early. Primary care providers should be vigilant, however, about evaluating infants in whom jaundice presents early, is prolonged beyond 2 weeks of life, or presents at high levels. Even in well-appearing infants, fractionated (direct and indirect) bilirubin levels should be obtained in these clinical scenarios to evaluate for potential cholestasis. This review presents an approach to the evaluation of a jaundiced infant and discusses diagnosis and management of several causes of neonatal cholestasis.
Key points
- •
The initial evaluation of a jaundiced infant should always include measuring serum conjugated (or direct) and unconjugated (or indirect) bilirubin levels.
- •
Jaundice in an infant that is of very early onset (less than 24 hours of age), persistent beyond 14 days of life, or of new-onset is abnormal and should be investigated.
- •
Conjugated hyperbilirubinemia in an infant (direct bilirubin levels >1.0 mg/dL or >17 μmol/L, or >15% of total bilirubin) is never normal and indicates hepatobiliary abnormality.
- •
Infants with cholestasis should be evaluated promptly for potentially life-threatening and treatable causes whereby timing of intervention directly impacts clinical outcomes.
Introduction
Jaundice in the neonate is common, usually secondary to unconjugated or indirect hyperbilirubinemia, and is most typically not dangerous to the infant. However, even in the setting of the well-appearing neonate, jaundice should be investigated if it is of very early onset (less than 24 hours of life), prolonged beyond 14 days of life, of new-onset, or at high levels. In these settings, it is critical to evaluate for potentially life-threatening causes, such as infection or evolving hepatobiliary dysfunction, and determine if urgent therapeutic intervention is required. Conjugated hyperbilirubinemia warrants expedient evaluation as timing of invention in some cases directly impacts clinical outcomes.
Bile is primarily composed of bile acids, bilirubin, and fats, is formed in the liver, and is secreted into the canaliculus. From the canaliculus, bile flows into biliary ducts from where it is ultimately secreted into the intestine after transient storage within the gallbladder. Disruption of this process at any level results in cholestasis. Cholestasis is the end result of obstruction of the normal excretion of bile from the liver, resulting in the abnormal accumulation of bile salts, bilirubin, and lipids in liver and the blood. Although cholestasis is not synonymous with conjugated hyperbilirubinemia, the abnormal retention of bilirubin, elevated serum levels in cholestasis, low cost, and wide availability of testing make serum-conjugated bilirubin the most clinically useful marker of cholestasis.
Clinically, cholestasis in the infant may present as jaundice, pruritus, fat-soluble vitamin deficiency, or may evolve during or following acute liver failure. Functional or anatomic biliary obstruction is often heralded by the presence of acholic stools. Although cholestasis is frequently the primary presenting symptom of neonatal hepatobiliary disease, it also commonly represents the final common pathway of any disease that affects the neonatal liver. As such, cholestasis is often classified by origin and is designated as either (1) biliary, referring to structural abnormalities and obstruction of extrahepatic or intrahepatic bile ducts; or (2) hepatocellular, resulting from impairment in bile transport, genetic or metabolic abnormalities, and infection.
This review presents an approach to the evaluation of the jaundiced infant. The authors discuss the most common causes, disease-specific evaluation, and clinical management of neonatal cholestasis. In addition, general concepts of supportive care for infants with cholestasis are reviewed.
Introduction
Jaundice in the neonate is common, usually secondary to unconjugated or indirect hyperbilirubinemia, and is most typically not dangerous to the infant. However, even in the setting of the well-appearing neonate, jaundice should be investigated if it is of very early onset (less than 24 hours of life), prolonged beyond 14 days of life, of new-onset, or at high levels. In these settings, it is critical to evaluate for potentially life-threatening causes, such as infection or evolving hepatobiliary dysfunction, and determine if urgent therapeutic intervention is required. Conjugated hyperbilirubinemia warrants expedient evaluation as timing of invention in some cases directly impacts clinical outcomes.
Bile is primarily composed of bile acids, bilirubin, and fats, is formed in the liver, and is secreted into the canaliculus. From the canaliculus, bile flows into biliary ducts from where it is ultimately secreted into the intestine after transient storage within the gallbladder. Disruption of this process at any level results in cholestasis. Cholestasis is the end result of obstruction of the normal excretion of bile from the liver, resulting in the abnormal accumulation of bile salts, bilirubin, and lipids in liver and the blood. Although cholestasis is not synonymous with conjugated hyperbilirubinemia, the abnormal retention of bilirubin, elevated serum levels in cholestasis, low cost, and wide availability of testing make serum-conjugated bilirubin the most clinically useful marker of cholestasis.
Clinically, cholestasis in the infant may present as jaundice, pruritus, fat-soluble vitamin deficiency, or may evolve during or following acute liver failure. Functional or anatomic biliary obstruction is often heralded by the presence of acholic stools. Although cholestasis is frequently the primary presenting symptom of neonatal hepatobiliary disease, it also commonly represents the final common pathway of any disease that affects the neonatal liver. As such, cholestasis is often classified by origin and is designated as either (1) biliary, referring to structural abnormalities and obstruction of extrahepatic or intrahepatic bile ducts; or (2) hepatocellular, resulting from impairment in bile transport, genetic or metabolic abnormalities, and infection.
This review presents an approach to the evaluation of the jaundiced infant. The authors discuss the most common causes, disease-specific evaluation, and clinical management of neonatal cholestasis. In addition, general concepts of supportive care for infants with cholestasis are reviewed.
Evaluation of the jaundiced infant
Jaundice in the infant is usually clinically evident when the total serum bilirubin level exceeds 2.5 to 3.0 mg/dL (42–51 μmol/L) and is seen as scleral icterus or yellowing of the oral mucosa. However, visual estimates of serum bilirubin levels are inadequate and not precise, and hence, levels should be determined when concern for elevation is raised. Although jaundice in neonates is common and can be physiologic, the continued presence of jaundice at 2 weeks of age should alert providers to the possibility of a pathologic process. A thorough examination and history evaluating for the possibility acute life-threatening conditions such as sepsis are paramount. In addition, clinical evaluation should survey for stigmata of hepatobiliary disease that may be heralded by the presence of dark urine or acholic stools or examination findings of hepatosplenomegaly and ascites. If the infant is exclusively breastfed and is well, the evaluation of serum bilirubin levels may be delayed up to 1 week (until 3 weeks of age) after repeat clinical evaluation. However, if the infant is ill appearing, is formula fed, or carries any additional “red flags” such as poor growth or dysmorphic features, the provider should obtain total and fractionated (direct and indirect) serum bilirubin levels. Conjugated hyperbilirubinemia in an infant (direct bilirubin levels >1.0 mg/dL or >17 μmol/L, or >15% of total bilirubin) is never normal and indicates hepatobiliary abnormality. The identification of elevated unconjugated hyperbilirubinemia warrants a different approach to management and is beyond the scope of this review.
If conjugated hyperbilirubinemia is identified, referral to a pediatric hepatologist is mandatory because timely identification of treatable causes of cholestasis can improve clinical outcomes. Secondary laboratory evaluations after cholestasis is identified may include serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase, prothrombin time and international normalized ratio (INR), and albumin levels. The initial diagnostic imagining should include an abdominal ultrasound (US), which can identify congenital anatomic or obstructive causes of cholestasis, including choledochal cysts and gallstones, and screen for vascular anomalies and evidence of portal hypertension such as splenomegaly. Liver biopsy often provides critical information to the diagnostic evaluation of neonates with cholestasis.
An algorithmic approach to the evaluation of the cholestatic infant is summarized in Fig. 1 . Specific causes of neonatal cholestasis are reviewed in the text and tabulated in Table 1 .
| Metabolic/genetic | Galactosemia Tyrosinemia type 1 Dubin-Johnson syndrome Rotor syndrome Disorders of BAD A1AT deficiency CF Defects of bile transport (PFIC) Peroxisomal disorders |
| Syndromic | Trisomy 21 Trisomy 13 Trisomy 18 Joubert syndrome Ivemark syndrome Beckwith-Weidemann syndrome Bardet-Biedl syndrome |
| Biliary | BA Choledochal cyst ALGS Choledocholithiasis Neonatal sclerosing cholangitis Caroli disease Obstruction from mass or stricture |
| Nutritional | Total parenteral nutrition |
| Cardiovascular | Heart failure Shock Hepatic ischemia |
| Infection | Herpes simplex virus Cytomegalovirus Adenovirus Hepatitis B Sepsis Urinary tract infection Cholecystitis Cholangitis |
| Endocrine | Hypothyroidism Panhypopituitarism Adrenal insufficiency |
Structural (Biliary) Causes of Neonatal Cholestasis
Biliary atresia
Biliary atresia (BA) is the most common cause of infantile obstructive cholangiopathy and most frequent indication for liver transplantation in the pediatric population. The reported incidence of BA is 0.5 to 3.2 per 10,000 live births, but varies based on geography and ethnicity. BA is characterized by progressive inflammation and fibrosis of the bile ducts, resulting in progressive obliteration of the extrahepatic and variably intrahepatic bile ducts. The cause of BA is currently unknown. Hypotheses regarding pathogenesis range from abnormal genetic programming of bile duct formation, to viral infections, toxins, or autoimmune-mediated chronic biliary inflammation.
BA is characterized anatomically, by the level of extrahepatic biliary obstruction. Two clinical phenotypes exist: “classical” BA, which is not associated with extrahepatic congenital anomalies, and “biliary atresia with splenic malformation” that presents with other congenital anomalies, most frequently situs inversus, asplenia, or polysplenia, cardiac malformations, and intestinal malrotation.
BA presents most commonly with cholestasis between 2 and 5 weeks of life. Acholic stools may be present and indicate biliary obstruction; however, onset commonly follows the onset of jaundice. Unfortunately, if an affected infant has a preceding history of physiologic jaundice, the development of cholestasis may go unrecognized and delay appropriate evaluation and management. This clinical scenario highlights the importance of evaluating any prolonged or new jaundice in infants. Infants with delayed evaluation or presentation may demonstrate signs of chronic liver disease with portal hypertension such as hepatosplenomegaly or ascites. As chronic inflammation and cholestasis lead to malabsorption, many infants with BA present with inadequate weight gain and are characterized as failure to thrive.
Expedient differentiation of BA from other causes of neonatal cholestasis is critical, because surgical intervention before 2 months of age has been shown to improve surgical success and clinical outcome. Without rapid intervention, the natural history of BA is uniform fatality secondary to progressive end-stage liver disease by 2 years of age. Early in the course of disease, infants with BA typically demonstrate conjugated hyperbilirubinemia (direct bilirubin 2–7 mg/dL with total bilirubin levels between 5 and 12 mg/dL), with elevations in transaminases (ALT, AST) and GGT; the GGT elevation is usually more significant than that of ALT because the focus of the hepatocellular injury is in the bile ducts.
Abdominal US is recommended early in the evaluation of a cholestatic infant. In the setting of BA, the US typically demonstrates absence, or nonfilling, of the gallbladder after adequate fasting, and an atretic extrahepatic bile duct; a normal gallbladder appearance, however, does not eliminate BA as the cause. The presence of an echogenic or fibrotic triangular cord at the porta hepatis representing the biliary remnant may be described as the “triangular cord sign” ( Fig. 2 ) and has a diagnostic sensitivity of 73%. Functional abdominal imaging, including hepatobiliary scintigraphy with technetium-labeled iminodiacetic acid derivatives (HIDA scan), can assist in the differentiation between obstructive and nonobstructive causes of neonatal cholestasis. Pretreatment with phenobarbital (5 mg/kg/d) for 5 days before HIDA scan may increase the sensitivity of this test, but specificity is limited. On HIDA, the demonstration of rapid update of tracer but absence of excretion into the bowel at 24 hours is suggestive of BA ( Fig. 3 ) or other obstructive process (eg, plugging in cystic fibrosis, CF); however, the low specificity (45%–72%) of the examination makes it better suited for exclusion rather than diagnosis of BA. A normal HIDA does eliminate BA from the differential of possible diagnoses. A false “positive” nonexcreting HIDA scan finding may result from functional causes of cholestasis such as hypothyroidism.
In many cases, percutaneous liver biopsy is helpful in excluding alternate causes of neonatal cholestasis. Histopathological findings supportive of a diagnosis of BA include demonstration of bile ductular proliferation and bile duct plugging with relative preservation of normal hepatic lobular architecture ( Fig. 4 ). Given the progressive nature of BA, however, the extent of liver fibrosis at the time of biopsy may vary, as can the extent of bile duct proliferation and destruction.
Failure to exclude BA, or a high suspicion for BA, necessitates surgical exploration with intraoperative cholangiogram. The diagnosis of BA is confirmed or excluded at the time of laparotomy, and intraoperative cholangiogram remains the gold standard for verifying a diagnosis of BA ; the identification of an atretic extrahepatic biliary tree confirms the diagnosis ( Fig. 5 ). If BA is confirmed, surgical intervention at the time of initial laparotomy and intraoperative cholangiogram, with a Kasai hepatic portoenterostomy, is recommended. The Kasai aims to restore bile flow from the liver to bowel by excising the biliary obstruction and establishing biliary drainage through an anastomosis of the jejunal limb of a Roux-en-Y with the liver at the porta hepatis. The younger the age of diagnosis of BA and Kasai, the more likely the Kasai will be successful. Although restoration of bile flow can significantly slow the progression of disease, most children progress to develop cirrhosis and portal hypertension despite effective bile drainage and ultimately require liver transplantation.
The importance of early diagnosis and surgical intervention implies a role for screening in the identification of BA. Screening for BA using stool color cards is currently used in Japan and Taiwan. Implementation of these programs, which use parents and caregivers to observe and report the infant’s stool color at 1 month of age, has improved the timeliness of diagnosis and resulted in a significantly higher proportion of infants undergoing portoenterostomy before 60 days of age. Stool color screening cards have not been widely adopted in North America or Europe, placing responsibility on primary care practitioners to have a high level of suspicion at the earliest routine well-child clinic visits.
Alagille syndrome
Alagille syndrome (ALGS) is a genetic disorder characterized by chronic, progressive cholestasis secondary to a paucity of intralobular bile ducts. The estimated prevalence is 1:30,000. ALGS is inherited in an autosomal dominant fashion, but may occur sporadically due to de novo mutation. Most individuals with ALGS carry a mutation in JAG1 , a gene located on chromosome 20, but a small number have mutations in NOTCH2 . The product of JAG1 and NOTCH2 is a ligand in the Notch signaling pathway, which plays a key role in embryogenesis.
Multiple organ systems are affected in infants with ALGS. Typically, ALGS is characterized by progressive cholestatic liver disease, stereotypical facial features, congenital heart disease, posterior embryotoxon, butterfly vertebrae, and renal disease. Most infants with ALGS present with cholestasis within the first 3 months of life. Those with severe congenital heart disease may present at birth or may initially come to attention after a cardiology evaluation. Although many forms of congenital heart disease have been associated with ALGS (eg, tetralogy of Fallot and transposition of the great arteries), the most common is peripheral pulmonary stenosis. The characteristic facial features are frequently difficult to appreciate in the neonatal period but include a prominent forehead and pointed chin, giving the face a triangular appearance, deep-set eyes with hypertelorism, and a saddle nose.
Care must be taken to discriminate ALGS from alternate causes of neonatal cholestasis, particularly BA. As in BA, standard neonatal cholestasis evaluation typically demonstrates conjugated hyperbilirubinemia associated with elevated serum aminotransferases and especially GGT, reflective of the biliary involvement. Recommended assessments for the extrahepatic manifestations include abdominal US, radiographs of the spine to identify hemivertebra or butterfly vertebra, echocardiogram, and ophthalmologic evaluation to identify the presence of posterior embryotoxon. Children with ALGS may also benefit from routine neuroimaging, because cerebrovascular anomalies, such as Moyamoya, resulting in increased risk of intracranial bleeding or stroke, have been described.
Although a liver biopsy is not required for diagnosis when other stereotypical syndromic features are present, histologic evaluation may be needed when the diagnosis is in question or hepatic disease advancement is suspected of being advanced. The histopathology in ALGS is characterized by bile ductular paucity. The number of bile ducts is normally diminished in preterm infants, however, so care must be taken to not to make the diagnosis of pathologic paucity incorrectly ( Fig. 6 ). In term infants and older children, the normal bile duct to portal tract ratio ranges from 0.9 to 1.8, with ratios less than 0.9 suggestive of paucity. Without the other features of ALGS, infants with cholestatic jaundice and elevated GGT usually require a liver biopsy, hepatobiliary scintigraphy, and possibly an intraoperative cholangiogram to verify patency of the extrahepatic biliary system; care must be taken to interpret the intraoperative cholangiogram correctly, because the extrahepatic bile ducts in ALGS are typically very small due to few feeding intrahepatic ducts, but they are patent.
